Lynn Kuo

Identification of Differentially Expressed Genes Between Osteoblasts and Osteocytes

Osteocytes represent the most abundant cellular component of mammalian bones with important functions in bone mass maintenance and remodeling. To elucidate the differential gene expression between osteoblasts and osteocytes we completed a comprehensive analysis of their gene profiles. Selective identification of these two mature populations was achieved by utilization of visual markers of bone lineage cells. We have utilized dual GFP reporter mice in which osteocytes are expressing GFP (topaz) directed by the DMP1 promoter, while osteoblasts are identified by expression of GFP (cyan) driven by 2.3 kb of the Col1a1 promoter. Histological analysis of 7-day-old neonatal calvaria confirmed the expression pattern of DMP1GFP in osteocytes and Col2.3 in osteoblasts and osteocytes. To isolate distinct populations of cells we utilized fluorescent activated cell sorting (FACS). Cell suspensions were subjected to RNA extraction, in vitro transcription and labeling of cDNA and gene expression was analyzed using the Illumina WG-6v1 BeadChip. Following normalization of raw data from four biological replicates, 3444 genes were called present in all three sorted cell populations: GFP negative, Col2.3cyan(+) (osteoblasts), and DMP1topaz(+) (preosteocytes and osteocytes). We present the genes that showed in excess of a 2-fold change for gene expression between DMP1topaz(+) and Col2.3cyan(+) cells. The selected genes were classified and grouped according to their associated gene ontology terms. Genes clustered to osteogenesis and skeletal development such as Bmp4, Bmp8a, Dmp1, Enpp1, Phex and Ank were highly expressed in DMP1topaz(+)cells. Most of the genes encoding extracellular matrix components and secreted proteins had lower expression in DMP1topaz(+) cells, while most of the genes encoding plasma membrane proteins were increased. Interestingly a large number of genes associated with muscle development and function and with neuronal phenotype were increased in DMP1topaz(+) cells, indicating some new aspects of osteocyte biology. Although a large number of genes differentially expressed in DMP1topaz(+) and Col2.3cyan(+) cells in our study have already been assigned to bone development and physiology, for most of them we still lack any substantial data. Therefore, isolation of osteocyte and osteoblast cell populations and their subsequent microarray analysis allowed us to identify a number or genes and pathways with potential roles in regulation of bone mass.

Bayesian Computation for Nonhomogeneous Poisson Processes in Software Reliability

Abstract A unified approach to the nonhomogeneous Poisson process in software reliability models is given. This approach models the epochs of failures according to a general order statistics model or to a record value statistics model. Their corresponding point processes can be related to the nonhomogeneous Poisson processes, for example, the Goel—Okumoto, the Musa—Okumoto, the Duane, and the Cox—Lewis processes. Bayesian inference for the nonhomogeneous Poisson processes is studied. The Gibbs sampling approach, sometimes with data augmentation and with the Metropolis algorithm, is used to compute the Bayes estimates of credible sets, mean time between failures, and the current system reliability. Model selection based on a predictive likelihood is studied. A numerical example with a real software failure data set is given.

Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer

Since the creation of Dolly via somatic cell nuclear transfer (SCNT), more than a dozen species of mammals have been cloned using this technology. One hypothesis for the limited success of cloning via SCNT (1%–5%) is that the clones are likely to be derived from adult stem cells. Support for this hypothesis comes from the findings that the reproductive cloning efficiency for embryonic stem cells is five to ten times higher than that for somatic cells as donors and that cloned pups cannot be produced directly from cloned embryos derived from differentiated B and T cells or neuronal cells. The question remains as to whether SCNT-derived animal clones can be derived from truly differentiated somatic cells. We tested this hypothesis with mouse hematopoietic cells at different differentiation stages: hematopoietic stem cells, progenitor cells and granulocytes. We found that cloning efficiency increases over the differentiation hierarchy, and terminally differentiated postmitotic granulocytes yield cloned pups with the greatest cloning efficiency.

Choosing among Partition Models in Bayesian Phylogenetics

Bayesian phylogenetic analyses often depend on Bayes factors (BFs) to determine the optimal way to partition the data. The marginal likelihoods used to compute BFs, in turn, are most commonly estimated using the harmonic mean (HM) method, which has been shown to be inaccurate. We describe a new more accurate method for estimating the marginal likelihood of a model and compare it with the HM method on both simulated and empirical data. The new method generalizes our previously described stepping-stone (SS) approach by making use of a reference distribution parameterized using samples from the posterior distribution. This avoids one challenging aspect of the original SS method, namely the need to sample from distributions that are close (in the Kullback–Leibler sense) to the prior. We specifically address the choice of partition models and find that using the HM method can lead to a strong preference for an overpartitioned model. In contrast to the HM method and the original SS method, we show using simulated data that the generalized SS method is strikingly more precise (repeatable BF values of the same data and partition model) and yields BF values that are much more reasonable than those produced by the HM method. Comparisons of HM and generalized SS methods on an empirical data set demonstrate that the generalized SS method tends to choose simpler partition schemes that are more in line with expectation based on inferred patterns of molecular evolution. The generalized SS method shares with thermodynamic integration the need to sample from a series of distributions in addition to the posterior. Such dedicated path-based Markov chain Monte Carlo analyses appear to be a cost of estimating marginal likelihoods accurately.

Bayesian semiparametric inference for the accelerated failure-time model

Bayesian semiparametric inference is considered for a loglinear model. This model consists of a parametric component for the regression coefficients and a nonparametric component for the unknown error distribution. Bayesian analysis is studied for the case of a parametric prior on the regression coefficients and a mixture-of-Dirichlet-processes prior on the unknown error distribution. A Markov-chain Monte Carlo (MCMC) method is developed to compute the features of the posterior distribution. A model selection method for obtaining a more parsimonious set of predictors is studied. The method adds indicator variables to the regression equation. The set of indicator variables represents all the possible subsets to be considered. A MCMC method is developed to search stochastically for the best subset. These procedures are applied to two examples, one with censored data.

Bayesian and profile likelihood change point methods for modeling cognitive function over time

Change point models are often used to model longitudinal data. To estimate the change point, Bayesian (Biometrika 62 (1975) 407; Appl. Statist. 41 (1992) 389; Biometrics 51 (1995) 236) or profile likelihood (Statist. Med. 19 (2000) 1555) methods may be used.We compare and contrast the two methods in analyzing longitudinal cognitive data from the Bronx Aging Study. The Bayesian method has advantages over the profile likelihood method in that it does not require all subjects to have the same change point. Caution must be taken regarding sensitivity to choice of prior distribution, identifiability, and goodness of fit. Analyses show that decline in memory precedes diagnosis of dementia by 7.5-8 years, and individual change points are not needed to model heterogeneity across subjects.

A Note on the Estimation of the Multinomial Logit Model With Random Effects

The multinomial logit model with random effects is often used in modeling correlated nominal polytomous data. Given that there is no standard software of fitting it, we advocate using either a Poisson log-linear model or a Poisson nonlinear model, both with random effects. Their implementations can be carried out easily by many existing commercial statistical packages including SAS. A brand choice dataset is used to illustrate the proposed methods.

Bayesian Binary Segmentation Procedure for a Poisson Process With Multiple Changepoints

We observe n events occurring in (0, T] taken from a Poisson process. The intensity function of the process is assumed to be a step function with multiple changepoints. This article proposes a Bayesian binary segmentation procedure for locating the changepoints and the associated heights of the intensity function. We conduct a sequence of nested hypothesis tests using the Bayes factor or the BIC approximation to the Bayes factor. At each comparison in the binary segmentation steps, we need only to compare a singlechangepoint model to a no-changepoint model. Therefore, this method circumvents the computational complexity we would normally face in problems with an unknown (large) number of dimensions. A simulation study and an analysis on a real dataset are given to illustrate our methods.

Bayesian Computation of Software Reliability

Abstract Bayesian methods for the Jelinski and Moranda and the Littlewood and Verrall models in software reliability are studied. A Gibbs sampling approach is employed to compute the Bayes estimates. In addition, prediction of future failure times and future reliabilities is examined. Model selection based on the mean squared prediction error and the prequential likelihood of the conditional predictive ordinates is developed.

Bayesian reliability modeling for masked system lifetime data

In the masked system lifetime data, the exact component that causes the systems failure is often unknown. For each series system at test, we observe its systems failure time and a set of components that includes the component actually causing the system to fail. The objective is to make inferences for the reliability of the components. In this paper we consider various probability models for the conditional masking probabilities that identify the set of possible failed components given the true cause of failure and the systems failure time. In addition to exponential distributions for the component lifetimes, we consider Weibull distributions. A Bayesian approach that uses Gibbs sampling will be developed for each of the models. Model selection by a predictive approach will also be developed. We show that improved inference can be obtained by modeling the masking probabilities.